Dataset Information

Salvage pathway maintains functional respiratory complex I

ABSTRACT: Regulation of the turnover of complex I (CI), the largest mitochondrial respiratory chain complex remains enigmatic, despite huge advancement in understanding its structure and the assembly steps in recent years. Although some studies indicated that CI might be remodelled in response to various stimuli, the mechanism mediating these putative changes is unknown. Here, we report that the NADH-oxidising N-module which sits on the tip of the CI peripheral arm is turned over at a higher rate and largely independently of the rest of the complex. The N-module turnover is mediated by mitochondrial matrix protease ClpXP, which selectively removes and degrades damaged core subunits. The observed mechanism seems to be a safeguard against accumulation of dysfunctional CI arising from inactivation of the N-module subunits due to attrition caused by extensive redox activity. This CI salvage pathway maintains highly functional CI and healthy mitochondria through an energetically favourable mechanism that demands much lower energetic cost than de novo synthesis and reassembly of the entire CI.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Cell Culture, Fibroblast

SUBMITTER: Karolina Szczepanowska

LAB HEAD: Aleksandra Trifunovic

PROVIDER: PXD014897 | Pride | 2020-03-05

REPOSITORIES: Pride

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Publications

A salvage pathway maintains highly functional respiratory complex I.

Szczepanowska Karolina K Senft Katharina K Heidler Juliana J Herholz Marija M Kukat Alexandra A Höhne Michaela Nicole MN Hofsetz Eduard E Becker Christina C Kaspar Sophie S Giese Heiko H Zwicker Klaus K Guerrero-Castillo Sergio S Baumann Linda L Kauppila Johanna J Rumyantseva Anastasia A Müller Stefan S Frese Christian K CK Brandt Ulrich U Riemer Jan J Wittig Ilka I Trifunovic Aleksandra A

Nature communications 20200402 1

Regulation of the turnover of complex I (CI), the largest mitochondrial respiratory chain complex, remains enigmatic despite huge advancement in understanding its structure and the assembly. Here, we report that the NADH-oxidizing N-module of CI is turned over at a higher rate and largely independently of the rest of the complex by mitochondrial matrix protease ClpXP, which selectively removes and degrades damaged subunits. The observed mechanism seems to be a safeguard against the accumulation ...[more]

PMID: 32242014

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Project description:We previously observed reduced graft survival for kidney transplants having interstitial fibrosis with subclinical inflammation, but not fibrosis alone, on 1-year protocol biopsy. The current study aimed to determine whether fibrosis with inflammation at 1 year is associated with renal functional decline in a low-risk transplant cohort and to characterize the nature of the inflammation. Subjects were living-donor, tacrolimus/mycophenolate-treated transplant recipients without overt risk factors for reduced graft survival (n=151). Transplants with normal histology (n=86) or fibrosis alone (n=45) on 1-year protocol biopsy had stable renal function between 1 and 5 years, while those having fibrosis with inflammation (n=20) had declining glomerular filtration rate and reduced graft survival. Immunohistochemistry confirmed increased interstitial T-cells and macrophages/dendritic cells in the fibrosis with inflammation group. Gene expression was performed on a subset of biopsies in each group and demonstrated increased expression of transcripts related to innate and cognate immunity in transplants having fibrosis with inflammation. Pathway- and pathological process-specific analyses of microarray profiles revealed that, in fibrosis with inflammation, over-expressed transcripts were enriched for potentially damaging immunological activities including Toll-like receptor signaling, antigen presentation/dendritic cell maturation, interferon gamma-inducible response, cytotoxic T lymphocyte-associated and acute rejection-associated genes. Thus, fibrosis with inflammation in 1-year protocol biopsies is associated with reduced graft survival and function and with a rejection-like gene expression signature even in recipients with no clinical risk for inferior outcome. Early interventions aimed at altering rejection-like inflammation may favor improved long-term KTx survival. We analyzed gene expression from a group of 65 renal transplant recipients. Patient groups were carefully selected to include patients on the same immunosuppression (Prograf-MMF-Pred), transplant type (LD), absence of over post-transplant complications (AR, BK, DGF). For each patient a 1 year protocol biopsy was examined by conventional histology and gene expression. By histology the patients were categorized as histologically normal (n=25, i/cg/ci=0), IF/TA (n=24, i/cg=0, ci>0) and IFTA+i (n=16, cg=0, i/ci>0). This dataset is part of the TransQST collection.

Dataset Information

Salvage pathway maintains functional respiratory complex I

Publications

A salvage pathway maintains highly functional respiratory complex I.

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